Anionic and cationic water soluble cyclodextrin derivatives salts can be made according to: 1) Japanese Patent No. JP 05001102 to Yoshinaga (sulfonic acid derivatives of cyclodextrins); 2) U.S. Pat. No. 5,241,059 to Yoshinaga (cyclodextrin derivatives containing sulfoalkyl ether (SAE), ammonium, phosphoric, carboxyl, hydroxyl, tosyl, t-butyl-dimethylsilyl (TBDMS), azide, trimethyl ammonium, or carboxyalkyl ether); 3) PCT International Publication No. WO 01/40316 to Zhang et al. (6-mercapto-cyclodextrin derivatives of the general formula CD-6-O—CH2—S—R—X, wherein R can be an alkylene group and X can be an —SO3H group, and the cyclodextrin can be α, β, or γ); 4) Adam et al. (J. Med. Chem. (2002), 45, 1806-1816) (CD derivatives containing sulfoalkyl (sulfomethyl, sulfoethyl, sulfopropyl)thio ether); 5) Tarver et al. (Bioorganic & Medicinal Chemistry (2002), 10, 1819-1827) (sulfoalkyl (sulfoethyl)thioalkyl ether cyclodextrin derivatives); 6) U.S. Pat. No. 5,594,125 to Seyschab (cyclodextrin derivatives having at least one lipophilic substituent and one hydrophilic radical per cyclodextrin molecule); 7) U.S. Pat. No. 5,760,015 and No. 5,846,954 to Joullie (“one-sided” water soluble cyclodextrin derivatives having at least 10 anionic groups on one side of the CD molecule); 8) U.S. Pat. No. 5,019,562 to Folkman (anionic CD derivatives having a sulfate, phosphate, or carboxylate group); 9) U.S. Pat. No. 5,183,809 to Weisz et al. (polyionic derivatives having a sulfate, phosphate, carboxylate or nitrate group); 10) U.S. Pat. No. 5,658,894 to Weisz et al. (polymeric CD derivatives, wherein the CD comprises anionic R groups selected from the group consisting of sulfate, phosphate, sulfonate, carboxylate and nitrate, and nonanionic R groups selected from the group consisting of H, alkyl, aryl, ester, ether, thioester, thioether); 11) European Publication No. 01950227 to Ren et al. (Hydroxypropyl ether-sulfobutyl ether cyclodextrin derivatives), all of the disclosures of which are hereby incorporated by reference.
Sulfoalkyl ether cyclodextrin (SAE-CD) derivatives are polyanionic, hydrophilic, water soluble cyclodextrins derivatized with sulfoalkyl ether functional groups. SAE-CD derivatives are commercially available from CyDex Pharmaceuticals, Inc. (Lenexa, Kans.). SAE-CD is currently marketed under the trademarks Captisol® and Advasep®. SAE-CD can be manufactured according to the process disclosed in U.S. Pat. No. 6,153,746 to Pfizer, Inc.
Captisol® has an average of about 7 sulfoalkyl ether substituents per cyclodextrin molecule. The anionic sulfobutyl ether substituent dramatically improves the aqueous solubility and safety of the parent cyclodextrin. Reversible, non-covalent, complexation of drugs with CAPTISOL® generally allows for increased solubility and, in some cases, increased stability of drugs in aqueous solutions.

Various embodiments of a sulfoalkyl ether cyclodextrin include eicosa-O-(methyl)-6G-O-(4-sulfobutyl)-β-cyclodextrin, heptakis-O-(sulfomethyl)-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin, heptakis-O-[1,1-dimethylethyl)dimethylsilyl]-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin, heptakis-O-(sulfomethyl)-tetradecakis-O-(3-sulfopropyl)-β-cyclodextrin, and heptakis-O-[1,1-dimethylethyl)dimethylsilyl]-tetradecakis-O-(sulfomethyl)-β-cyclodextrin. Other known ether cyclodextrin derivatives containing a sulfoalkyl moiety include sulfoalkylthio and sulfoalkylthioalkyl ether derivatives such as octakis-(S-sulfopropyl)-octathio-γ-cyclodextrin, octakis-O-[3-[2-sulfoethyl)thio]propyl]-β-cyclodextrin], and octakis-S-(2-sulfoethyl)-octathio-γ-cyclodextrin.
The preparation of SAE-CD derivatives is disclosed in U.S. Pat. No. 5,376,645 and No. 5,134,127 to Stella et al. The SAE-CD derivatives or CD derivatives containing a sulfonate functional group can also be made according to Parmerter et al. (U.S. Pat. No. 3,426,011), Gadelle et al. (U.S. Pat. No. 5,578,719), Joullie et al. (U.S. Pat. No. 5,760,015 and U.S. Pat. No. 5,846,954), Buchanan et al. (U.S. Pat. No. 6,610,671 and U.S. Pat. No. 6,479,467), Perrier et al. (U.S. Pat. No. 6,524,595), Uchiyama et al. (U.S. Pat. No. 5,512,665), Lammers et al. (Recl. Tray. Chim. Pays-Bas (1972), 91(6), 733-742); Staerke (1971), 23(5), 167-171), Qu et al. (J. Inclusion Phenom. Macro. Chem., (2002), 43, 213-221), Yoshinaga (Japanese Patent No. JP 05001102; U.S. Pat. No. 5,241,059), Zhang et al. (PCT International Publication No. WO 01/40316), Adam et al. (J. Med. Chem. (2002), 45, 1806-1816), Tarver et al. (Bioorganic & Medicinal Chemistry (2002), 10, 1819-1827), Matos et al. (PCT International Publication No. WO 09/18069), Pipkin et al. (PCT International Publications No. WO 05/104712 and No. 07/50075), and Shah et al. (U.S. Pat. No. 6,153,746), the entire disclosures of which are hereby incorporated by reference.
Water soluble cyclodextrin derivatives can also be made according to: 1) Japanese Patent No. JP 05001102 to Yoshinaga (sulfonic acid derivatives of cyclodextrins); 2) U.S. Pat. No. 5,241,059 to Yoshinaga (cyclodextrin derivatives containing sulfoalkyl ether (SAE), ammonium, phosphoric, carboxyl, hydroxyl, tosyl, t-butyl-dimethylsilyl (TBDMS), azide, trimethyl ammonium, or carboxyalkyl ether); 3) PCT International Publication No. WO 01/40316 to Zhang et al. (6-mercapto-cyclodextrin derivatives of the general formula CD-6-O—CH2—S—R—X, wherein R can be an alkylene group and X can be an —SO3H group, and the cyclodextrin can be α, β, or γ); 4) Adam et al. (J. Med. Chem. (2002), 45, 1806-1816) (CD derivatives containing sulfoalkyl (sulfomethyl, sulfoethyl, sulfopropyl)thio ether); 5) Tarver et al. (Bioorganic & Medicinal Chemistry (2002), 10, 1819-1827) (sulfoalkyl (sulfoethyl)thioalkyl ether cyclodextrin derivatives); 6) U.S. Pat. No. 5,594,125 to Seyschab (cyclodextrin derivatives having at least one lipophilic substituent and one hydrophilic radical per cyclodextrin molecule); 7) U.S. Pat. No. 5,760,015 and U.S. Pat. No. 5,846,954 to Joullie (“one-sided” water soluble cyclodextrin derivatives having at least 10 anionic groups on one side of the CD molecule); 8) U.S. Pat. No. 5,019,562 to Folkman (anionic CD derivatives having a sulfate, phosphate, or carboxylate group); 9) U.S. Pat. No. 5,183,809 to Weisz et al. (polyionic derivatives having a sulfate, phosphate, carboxylate or nitrate group); 10) U.S. Pat. No. 5,658,894 to Weisz et al. (polymeric CD derivatives, wherein the CD comprises anionic R groups selected from the group consisting of sulfate, phosphate, sulfonate, carboxylate and nitrate, and nonanionic R groups selected from the group consisting of H, alkyl, aryl, ester, ether, thioester, thioether); 11) alkyl ether derivatized cyclodextrins (AE-CD's) (see Fromming and Szejtli, Cyclodextrins in Pharmacy, Kluwer Academic Publishing, Dordrecht, 1994 and references therein); 12) U.S. Pat. No. 5,536,826 to Hirsenkorn or U.S. Pat. No. 4,638,058 to Brandt et al. (aminoalkyl ether cyclodextrin (AAE-CD) derivatives), the entire disclosures of all the above being hereby incorporated by reference.
All of the currently available forms of anionic CD derivatives include metal salts and amine (non-quaternary amine) salts. Some SAE-CD salts include cations selected from the group consisting of alkali metals (e.g. Li+, Na+, K+), alkaline earth metals (e.g., Ca+2, Mg+2), and amine cations such as the cations of (C1-C6)-alkylamines, piperidine, pyrazine, (C1-C6)-alkanolamine, ethylenediamine, and (C4-C8)-cycloalkanolamine. Quaternary amine salts of anionic water soluble cyclodextrin derivatives have not been prepared.
Salts comprising a quaternary ammonium cation and a sulfate-based or sulfonate-based anion are known: PCT International Application Serial No. PCT/EP02/10206 filed Sep. 11, 2002 and published as PCT International Publication No. WO 03/022812 on Mar. 20, 2003; U.S. application Ser. No. 10/930,674 and Ser. No. 11/262,941.
The term “ionic liquids” has been understood to mean salts or mixtures of salts whose melting point is below 100° C. (P. Wasserscheid, W. Keim, Angew. Chem. 2001, 112, 3926); however, such a definition is not absolute. Exemplary ionic liquids include anions, such as halogenostannates, halogenoaluminates, hexafluorophosphates or tetrafluoroborates combined with substituted ammonium cations, phosphonium cations, pyridinum cations or imidazolium cations to thereby form salts. The use of ionic liquids in synthetic reactions has been described by Wasserscheid et al. (Ionic Liquids in Synthesis; eds. Peter Wasserscheid, Thomas Welton, 2003, Wiley-VCH Verlag GmbH & Co. KGaA, Germany). Several publications have already described the use of ionic liquids as solvents for chemical reactions (T. Welton, Chem. Rev. 1999, 99, 2071; P. Wasserscheid, W. Keim, Angew. Chem., 2000, 112, 3926). For example, hydrogenation reactions of olefins with rhodium(I) (P. A. Z. Suarez, J. E. L. Dullius, S. Einloft, R. F. de Souza and J. Dupont, Polyhedron 15/7, 1996, 1217-1219), ruthenium(II) and cobalt(II) complexes (P. A. Z. Suarez, J. E. L. Dullius, S. Einloft, R. F. de Souza and J. Dupont, Inorganica Chimica Acta 255, 1997, 207-209) have been carried out successfully in ionic liquids with tetrafluoroborate anion. The hydroformylation of functionalized and non-functionalized olefins is possible with rhodium catalysts in ionic liquids with weakly coordinating anions (e.g. PF6−, BF4−) (Y. Chauvin, L. Mussmann, H. Olivier, European Patent, EP 776880, 1997; Y. Chauvin, L. Mussmann, H. Olivier, Angew. Chem., Int. Ed. Engl., 1995, 34, 2698; W. Keim, D. Vogt, H. Waffenschmidt, P. Wasserscheid, J. of Cat., 1999, 186, 481).
Ionic liquids can also be used as extraction agents (solvents) for material separation (J. G. Huddleston, H. D. Willauer, R. P. Swatloski, A. E. Visser, R. D. Rogers, Chem. Commun. 1998, 1765-1766; b) A. E. Visser, R. P. Swatlowski, R. D. Rogers, Green Chemistry 2000, 2(1), 1-4) and as heat carriers (M. L. Mutch, J. S. Wilkes, Proceedings of the Eleventh International Symposium on Molten Salts, P. C. Trulove, H. C. De Long, G. R. Stafford and S. Deki (Hrsg.), Proceedings Volume 98-11, The Electrochemical Society, Inc, Pennington, N.J.; 1998, page 254).